# Regulation of Gene Expression During Stress

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $526,731

## Abstract

Proteostasis is achieved by a cellular network that coordinates protein synthesis, folding and degradation. Aging, transient fluctuations or persistent exposure to environmental or intracellular perturbants of proteostasis can lead to onset of disease, such as neurodegeneration and diabetes. Proteostasis during stress is largely maintained by adaptations in cellular capacity for protein synthesis and folding, thus avoiding the accumulation of damaged proteins that may result in deleterious effects on cell fate. Specifically, the Unfolded Protein Response (UPR) is a stress response that can rapidly change the capacity of the proteostasis network. However, there is a knowledge gap on the stress sensing and adaptation mechanisms during persistent UPR, before development of disease. We propose that the adaptive UPR during persistent stress exposure comprises the coordinated action of transcriptional, translational and metabolic reprogramming that maintains essential cellular functions and stress sensing while preventing cell death caused by ER dysfunction. We propose (i) Characterize a novel mechanism of adaptation to chronic stress using physiologically relevant models of persistent ER stress induction in pancreatic β cells. (ii) Determine the molecular mechanism of proinsulin mRNA translation in pancreatic β cells during persistent ER stress and (iii) Characterize a novel adaptive mechanism of increased glucose-stimulated insulin secretion (GSIS) during persistent ER stress in pancreatic β cells via the upregulation of the nutrient-sensing mitochondrial GTP dependent pathway.

## Key facts

- **NIH application ID:** 10219234
- **Project number:** 5R01DK053307-24
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** MARIA HATZOGLOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $526,731
- **Award type:** 5
- **Project period:** 1998-01-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219234

## Citation

> US National Institutes of Health, RePORTER application 10219234, Regulation of Gene Expression During Stress (5R01DK053307-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10219234. Licensed CC0.

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